A phase II and biomarker study of sorafenib combined with modified FOLFOX in patients with advanced hepatocellular carcinoma

Purpose: Sorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC). The phase III SHARP trial showed a median time-to-progression (mTTP) of 5.5 months, overall response rate (ORR) of 2%, and median overall survival (mOS) of 10.7 months with sorafenib. FOLFOX4 has shown modest activity in advanced HCC. We evaluated the combination of sorafenib and modified (m)FOLFOX in a single-arm, multicenter phase II study. Patients and Methods: The study included Child–Pugh A patients with advanced HCC and no prior systemic therapies. Patients received sorafenib 400 mg twice a day for 2 weeks, followed by concurrent mFOLFOX [5-fluorouracil (5-FU) 1,200 mg/m²/day for 46 hours, leucovorin 200 mg/m², and oxaliplatin 85 mg/m² biweekly]. The primary endpoint was mTTP with an alternative hypothesis of 7 months, and secondary endpoints included ORR, mOS, and circulating biomarkers. Results: The study enrolled 40 patients: HCV/EtOH/HBV, 43%/28%/13%; Child–Pugh A5, 70%. Notable grade 3/4 adverse events (AE) included AST/ALT elevation (28%/ 15%), diarrhea (13%), hyperbilirubinemia (10%), hand–foot syndrome (8%), and bleeding (8%). mTTP was 7.7 months [95% confidence interval (CI): 4.4–8.9], ORR 18%, and mOS 15.1 months (7.9–16.9). Sorafenib þ mFOLFOX increased plasma PlGF, VEGF-D, sVEGFR1, IL12p70, and CAIX and CD4^þ and CD8^þ effector T lymphocytes and decreased plasma sVEGFR2 and s-c-KIT and regulatory T cells (Tregs). Shorter TTP was associated with high baseline sVEGFR1. Shorter TTP and OS were associated with increases in Tregs and CD56^Dim natural killer (NK) cells after sorafenib alone and plasma sMET after combination treatment (all P < 0.05). Conclusions: Sorafenib þ mFOLFOX met the prespecified endpoint with encouraging efficacy but moderate hepatotoxicity. Thus, this regimen may be effective in select patients with adequate liver reserve. Biomarker evaluations suggested a correlation between time-to-progression (TTP) and angiogenic biomarkers and circulating Tregs.